Indole aryl sulfone derivative as well as preparation method and application thereof
A kind of technology of indole aryl sulfone, derivative
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Embodiment 1
[0049] Example 1: Preparation of intermediate 5-chloro-3-((3,5-dimethylphenyl)sulfanyl)-1H-indole-2-carboxylic acid ethyl ester (2)
[0050] 5-Chloro-1H-indole-2-carboxylic acid ethyl ester (1, 0.5g, 2.13mmol, 1eq.), 3,5-dimethylbenzenethiol (280μL, 2.13mmol, 1eq.), 1 -Chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (0.83g, 2.55mmol, 1.1eq.), acetonitrile (25mL) were added to the Bottom flask, stirred at room temperature for 6 hours; after the reaction was completed, the solvent of the reaction solution was evaporated to dryness, added dichloromethane (15mL) and saturated sodium chloride solution (50mL) for extraction, and the aqueous phase was extracted twice with dichloromethane (15mL) , combined the organic phases, added anhydrous magnesium sulfate to dry, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography (eluent ethyl acetate:petroleu...
Embodiment 2
[0053] Example 2: Preparation of intermediate 5-chloro-3-((3,5-dimethylphenyl)sulfonyl)-1H-indole-2-carboxylic acid ethyl ester (3)
[0054] Intermediate 2 (0.1g, 0.277mmol, 1eq.) was dissolved in 10mL of dichloromethane, and it was stirred in an ice bath, and m-chloroperoxybenzoic acid (0.143g, 0.831mmol , 3eq.). After 30 minutes, remove the ice bath, and stir the reaction at room temperature; after 4 hours, the reaction is complete, add 20 mL of dichloromethane to dilute, then add saturated sodium bisulfite solution for washing (10 mL×3), combine the organic phases, add saturated carbonic acid Sodium hydrogen solution was washed (10mL × 3), and finally washed with saturated sodium chloride solution (10mL), the organic phase was separated, dried by adding anhydrous magnesium sulfate, filtered, the filtrate was concentrated, and separated by silica gel column chromatography (ethyl acetate : Petroleum ether=1:4) to obtain intermediate 5-chloro-3-((3,5-dimethylphenyl)sulfonyl)-...
Embodiment 3
[0057] Example 3: Preparation of intermediate 5-chloro-3-((3,5-dimethylphenyl)sulfonyl)-1H-indole-2-carboxylic acid (4)
[0058] Intermediate 3 (0.1g, 0.255mmol, 1eq.) was dissolved in a mixed solvent of tetrahydrofuran / water (1:1, 10mL), and lithium hydroxide (32mg, 0.765mmol, 3eq.) was added under stirring at room temperature, at 45°C Stir for 8 hours; after the reaction is completed, evaporate most of the solvent under reduced pressure, and then add 1N dilute HCl solution dropwise to adjust the pH to 3-4. During this process, white insoluble matter is formed, and the intermediate is obtained after suction filtration and drying of the filter cake. 5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-1H-indole-2-carboxylic acid (4), yield: 66%, white solid, melting point: 270°C decomposed.
[0059] Spectral data:
[0060] 1 H NMR (400MHz, DMSO-d 6 )δ14.22(s,1H,COOH),13.10(s,1H,NH),8.21(s,1H,Ph-H),7.63(s,2H,Ph-H),7.56(d,J=8.7 Hz,1H,Ph-H),7.40(d,J=8.8Hz,1H,Ph-H),7.26(s,1H,Ph-H),2.31(s...
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